Mast cells and basophils are key contributors to allergies and other inflammatory diseases since they are the most prominent source of histamine as well as numerous additional inflammatory mediators which drive inflammatory responses. However, a closer understanding of their precise roles in allergies and other pathological conditions has been marred by the considerable heterogeneity that these cells display, not only between mast cells and basophils themselves but also across different tissue locations and species. While both cell types share the ability to rapidly degranulate and release histamine following high-affinity IgE receptor cross-linking, they differ markedly in their ability to either react to other stimuli, generate inflammatory eicosanoids or release immunomodulating cytokines and chemokines. Furthermore, these cells display considerable pharmacological heterogeneity which has stifled attempts to develop more effective anti-allergic therapies. Mast cell- and basophil-specific transcriptional profiling, at rest and after activation by innate and adaptive stimuli, may help to unravel the degree to which these cells differ and facilitate a clearer understanding of their biological functions and how these could be targeted by new therapies.